Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Abstract Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, "slug-flow" regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.

Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2 -dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever.

BACKGROUND AND PURPOSE: The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACH: Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 µg·kg(-1) ), Tsv (150 µg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa. KEY RESULTS: In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONS: The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone.

Simultaneous determination of dipyrone metabolites in rat hypothalamus, cerebrospinal fluid and plasma samples by LC-MS/MS.

BACKGROUND: After oral administration dipyrone is rapidly hydrolyzed to 4-methylaminoantipyrine, which is absorbed and further metabolized to 4-formylaminoantipyrine and to 4-aminoantipyrine, which is acetylated by a polymorphic N-acetyltransferase system to 4-acetylaminoantipyrine. To evaluate the presence of dipyrone metabolites in different rat matrices after intraperitoneal administration, an analytical method was developed and validated. METHODOLOGY: The four main dipyrone metabolites were extracted from plasma, cerebrospinal fluid and hypothalamus samples by LLE prior to LC-MS/MS. RESULTS: Standard calibration graphs for all metabolites were linear (r > 0.99). The intra- and inter-day precision and accuracy values were both inferior to 15%. CONCLUSION: This method is simple and specific for studying dipyrone metabolites after intraperitoneal administration.

Benign osteoblastoma of the sphenoid bone.

Osteoblastoma is an uncommon benign bone tumor that accounts for 1% of all primary bone tumors. Well documented in the spine and long bones, it is rarely found in the skull, namely in the sphenoid bone, with only five cases reported in the literature. We report a case of an 11-year-old girl with a histologically confirmed benign osteoblastoma in an unusual location and an atypical aspect on the imaging studies.

Fibrous dysplasia of the first cervical vertebra.

STUDY DESIGN: Case report. OBJECTIVE: To describe a case of monostotic fibrous dysplasia of the first cervical vertebra. SUMMARY OF BACKGROUND DATA: Fibrous dysplasia is a disorder of bone development of unknown etiology in which cancellous bone is replaced with fibrous tissue, resulting in expansion of the bone. The disease presents in either a monostotic or polyostotic form. Although fibrous dysplasia can involve any bone in the body, vertebral involvement is quite unusual. METHODS: A case of monostotic fibrous dysplasia of the first cervical vertebra is presented. RESULTS: A 53 year-old woman presented with a 1-month history of occipito-cervicalgia associated with great restriction of neck movements. Computed tomography and magnetic resonance imaging revealed an expansile, destructive lesion involving the right lateral mass of the first cervical vertebra, without involvement of the spinal cord. She was submitted to surgery and the lesion was removed. Microscopic examination was consistent with the diagnosis of fibrous dysplasia. Four years after surgery there was no clinical or imagiological recurrence. CONCLUSION: Although there are descriptions of vertebral fibrous dysplasia, this is the 12th case of monostotic fibrous dysplasia of the cervical spine described in the literature. Computed tomography and magnetic resonance imaging were essential for making the preoperative diagnosis.

Rosette-forming glioneuronal tumor: pathology case report.

OBJECTIVE: Rosette-forming glioneuronal tumor is a newly described mixed glial and neuronal tumor. We describe two cases and review the literature to better characterize this entity. METHODS: Patients were surgically treated, and tumors were diagnosed by light microscopy and immunohistochemistry using the avidin-biotin complex method. PubMed was searched for previously reported cases. RESULTS: Patient 1 was a 38-year-old woman who presented with headaches and no neurological abnormality. Magnetic resonance imaging showed a solid mass in the fourth ventricle. Subtotal excision of the mass caused transient gait ataxia. Patient 2 was a 51-year-old woman with dizziness who fell and sustained head trauma. Magnetic resonance imaging revealed a right paramedian cerebellar cystic and nodular mass and a separate nodule in the vermis, which were excised gross totally with no morbidity. Microscopic examination showed neuroepithelial tumors composed of neurocytic cells focally forming well-defined rosettes that were immunopositive for neuronal markers and of elongated, glial fibrillary acidic protein-immunoreactive astrocytes. No histological anaplasia was present. Both patients were well 18 and 8 months after surgery, respectively. Eighteen rosette-forming glioneuronal tumors were identified with the literature search. CONCLUSION: These are tumors of young adulthood (range, 12-59 yr) usually in or close to the fourth ventricle. Histologically, they are low-grade, although multiple foci or local extension may prevent total excision and account for some recurrences. On imaging, they are cystic, solid, or both, with minimal perilesional edema or mass effect. They are composed of neurocytic and glial elements, probably arising from a common progenitor in the subependymal plate, and need to be differentiated from a variety of glioneuronal tumors.

[Clinical application of functional MR. Evaluation of motor functions and verbal fluency]. / Aplicação clínica da RM funcional. Avaliação de funções motoras e fluência verbal.

In this article we reviewed some examples of our experience in clinical applications of functional MRI (fMRI) in the motor and verbal fluency tasks evaluation. Seventeen patients with supratentorial cerebral pathology (5 arteriovenous malformations--AVMs, 2 meningiomas, 1 tuberculoma, 1 cortical tuberoma, 1 DNET, 2 cerebral metastases, 3 gliomas and 2 patients with mesial temporal sclerosis and medically intractable epilepsy--lateralization of language) and three healthy subjects were studied on a 1.5 T system (Signa GE) using a blood oxygen level-dependent (BOLD)--sensitive multi-slice EPI technique. Different paradigms for localization of the motor (hand/foot) and verbal fluency sensorimotor cortex were tested and selected for each pathology. In healthy subjects motor activation elicited BOLD signal changes in the sensorimotor cortex, permitting identification of primary motor and sensory cortical areas and focal activation of different cortical areas by a verbal fluency task. Twelve motor studies were performed and in 6 RMF results demonstrated the localization of motor hand areas near the lesion, and in nine studies of verbal fluency 6 activation were adjacent to the lesion. The studies were performed prior to neurosurgical procedures, contributed to therapeutical decisions and proved to be a valuable non invasive method of cortical mapping for preoperative planning.